The H3Africa Kidney Disease Cohort Study

H3Africa 肾脏疾病队列研究

• 批准号: 10001248
• 负责人: Dwomoa Adu
• 金额: $ 59.41万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10001248
• 关键词: Affect; Africa; Africa South of the Sahara; African; African American; African Trypanosomiasis; American; Apolipoproteins; Basic Science; Biopsy; Blood; Case-Control Studies; Cessation of life; Chronic Disease; Chronic Hepatitis C; Chronic Kidney Failure; Clinical; Clinical Research; Cohort Studies; Controlled Study; Country; DNA; Data; Diabetes Mellitus; Dialysis procedure; Disease; Disease Progression; End stage renal failure; Ethiopia; Etiology; Focal Segmental Glomerulosclerosis; Formulation; Funding; Genes; Genetic; Genetic Determinism; Genetic Predisposition to Disease; Ghana; HIV Seronegativity; Health; Hepatitis B; Hepatitis B Virus; Hepatitis C virus; Heredity; High Prevalence; Human; Hypertension; Incidence; Individual; Infection; Intervention Trial; Investigation; Joints; Kenya; Kidney; Kidney Diseases; Kidney Transplantation; Longitudinal cohort study; Malaria; Membranous Glomerulonephritis; Natural History; Nigeria; Not Hispanic or Latino; Outcome; Parasites; Participant; Pathogenesis; Pattern; Phenotype; Population; Prevention strategy; Prospective cohort study; RNA; Renal glomerular disease; Reporting; Research; Research Infrastructure; Research Personnel; Resources; Risk; Risk Factors; Role; Sample Size; Science; Secondary to; Serum; Sickle Cell Anemia; Specimen; Susceptibility Gene; Teaching Hospitals; Therapeutic Intervention; Therapeutic Trials; Tissues; Translational Research; Trypanosoma; Trypanosomiasis; United States National Institutes of Health; Universities; Urine; Variant; Wit; Work; design; effective therapy; gene environment interaction; genetic variant; high risk; infection risk; innovation; insight; kidney biopsy; lifetime risk; modifiable risk; nephrogenesis; new therapeutic target; novel; public health relevance; repository; research study; risk variant; screening; screening program; translational study; treatment strategy

 DESCRIPTION (provided by applicant): African Americans (AA) have a greater than three-fold higher lifetime risk of end stage renal disease (ESRD) as compared to non-Hispanic Whites (7.8% to 2.8%) secondary to a higher prevalence of both chronic kidney disease (CKD) and glomerulonephritides (GN). Recent studies suggest that Blacks living in Sub-Saharan Africa (SSA) (African Blacks) may have a similarly high predilection to kidney disease as do AA and that underlying this similarity in the two populations (American and African Blacks) may be common genetic predispositions to kidney disease; the most notable of which are the APOL1 kidney risk variants that encode for apolipoprotein L1. Circulating apolipoprotein L1 acts as a trypanolytic factor capable of killing trypanosome parasites in human serum and may be protective against trypanosomiasis ("African sleeping sickness") which is endemic in 36 African countries. It is estimated that more than three million AA and greater than 50 million African Blacks have CKD due to clinically defined nephropathies (from hypertension, diabetes mellitus, sickle disease, etc.) and GN. A significant fraction of these will progress to ESRD which is a harbinger of imminent death in the African setting due to the scarcity of dialysis or kidney transplantation. Building on our work in AA (Parsa A. N Eng J Med 2013;369(23):2183-960 & Lipkowitz MS. Kidney Int 2013;83(1):114-20) as well as in African Blacks (Science 2014;344(6190):1346-9 & Tayo BO. Int Urol Nephrol 2013;45(2)485-94), we herein propose to leverage the resources and expertise in the ongoing, NIH-funded, case-controlled H3Africa Kidney Disease Study to conduct a multinational prospective cohort study in 3,000 participants with clinically defined nephropathies and in 1,000 participants with biopsy-confirmed incident glomerular disease (for a total sample size of 4,000 HIV-negative African Blacks with kidney disease) to accomplish the following research objectives: (1) determine whether APOL1 risk variants independently predict kidney disease progression and identify modifiable risk factors for kidney disease progression in African Blacks; (2) elucidate the causative role of gene-environment interactions (APOL1-infections) and their joint and several effects on the outcomes of GN among African Blacks by country (n=4) and region (East vs. West Africa) and (3) establish a high quality resource (data and specimen repository of blood, urine, DNA, RNA and kidney tissue) for basic, clinical and translational research in kidney disease and other chronic diseases. The proposed study is innovative in that it is the first adequately powered prospective cohort study to both identify the genetic determinants and characterize the phenotype for kidney disease progression in SSA. The overall impact of the study is likely to be very high as it would: (i) yield new information relevant for the development of kidney disease screening programs, preventative strategies and therapeutic intervention trials and (ii) create a new platform essentia for basic, clinical and translational studies of kidney disease in all people of African ancestry. o wit, this unique research resource would be made readily accessible to researchers worldwide.

 描述（由申请人提供）：与非西班牙裔白人（7.8％至2.8％）相比，非裔美国人（AA）患终末期肾病（ESRD）的终生风险高出三倍以上，这是由于慢性肾病（CKD）和肾小球肾病（GN）的患病率较高。最近的研究表明，生活在撒哈拉以南非洲 (SSA) 的黑人（非洲黑人）可能与 AA 一样，对肾脏疾病有较高的患病率，而这两个人群（美国和非洲黑人）的这种相似性背后可能是肾脏疾病的常见遗传倾向；其中最值得注意的是编码载脂蛋白 L1 的 APOL1 肾脏风险变异。循环载脂蛋白 L1 充当锥虫分解因子，能够杀死人血清中的锥虫寄生虫，并可能预防在 36 个非洲国家流行的锥虫病（“非洲昏睡病”）。据估计，超过 300 万 AA 和超过 5000 万非洲黑人因临床定义的肾病（高血压、糖尿病、镰状病等）和肾小球肾炎而患有 CKD。其中很大一部分将进展为终末期肾病（ESRD），这是非洲地区由于缺乏透析或肾移植而即将死亡的先兆。以我们在 AA（Parsa A. N Eng J Med 2013;369(23):2183-960 & Lipkowitz MS. Kidney Int 2013;83(1):114-20）以及非洲黑人（Science 2014;344(6190):1346-9 & Tayo BO. Int Urol Nephrol）的工作为基础2013;45(2)485-94)，我们在此 提议利用正在进行的、由 NIH 资助的病例对照 H3Africa 肾病研究中的资源和专业知识，对 3,000 名临床明确的肾病参与者和 1,000 名活检确诊的肾小球疾病参与者（总样本量为 4,000 名患有肾病的 HIV 阴性非洲黑人）进行跨国前瞻性队列研究，以实现以下研究目标： (1) 确定 APOL1 风险变异是否独立预测肾脏疾病进展，并确定非洲黑人肾脏疾病进展的可改变危险因素； (2) 阐明基因-环境相互作用（APOL1 感染）的致病作用及其对按国家（n=4）和地区（东非与西非）分列的非洲黑人肾小球肾炎结果的共同影响和（3）为肾脏疾病和其他慢性病的基础、临床和转化研究建立高质量资源（血液、尿液、DNA、RNA 和肾组织的数据和样本存储库） 疾病。拟议的研究具有创新性，因为它是第一个充分有力的前瞻性队列研究，既确定了 SSA 肾脏疾病进展的遗传决定因素，又描述了表型特征。这项研究的总体影响可能非常大，因为它将：（i）产生与肾脏疾病筛查计划、预防策略和治疗干预试验的制定相关的新信息，以及（ii）为所有非洲血统的肾脏疾病的基础、临床和转化研究创建一个新的基础平台。也就是说，全世界的研究人员都可以轻松获取这一独特的研究资源。